EP3057615B1 - Anti-rspo-antikörper und verfahren zur verwendung - Google Patents

Anti-rspo-antikörper und verfahren zur verwendung Download PDF

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EP3057615B1
EP3057615B1 EP14790974.1A EP14790974A EP3057615B1 EP 3057615 B1 EP3057615 B1 EP 3057615B1 EP 14790974 A EP14790974 A EP 14790974A EP 3057615 B1 EP3057615 B1 EP 3057615B1
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seq
hvr
amino acid
acid sequence
antibody
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EP3057615A2 (de
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Elaine STORM
Frederic J. De Sauvage
Jeremy M. Murray
Cameron L. NOLAND
Yan Wu
Christine Tan
Jo-Anne Hongo
Yongmei Chen
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F Hoffmann La Roche AG
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    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6843—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3046—Stomach, Intestines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
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    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
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    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
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    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/75—Agonist effect on antigen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • the antibody does not inhibit the interaction of RSPO3 with one or more of LGR4, LGR5, and/or LGR6 (e.g ., enhances binding of RSPO3 to one or more of LGR4, LGR5, and/or LGR6). In some embodiments, the antibody inhibits the interaction of RSP02 with one or more of LGR4, LGR5, and/or LGR6. In some embodiments, the antibody does not inhibit the interaction of RSPO2 with one or more of LGR4, LGR5, and/or LGR6 (e.g., enhances binding of RSPO2 to one or more of LGR4, LGR5, and/or LGR6).
  • the RSPO3 epitope comprises amino acid residues of RSPO3: Ser49, Asn52, Cys54, Leu55, Ser56, Phe63, Leu65, Gln72, Ile73, Gly74, Tyr84, Tyr89, Pro90, Asp91, Ile92, Lys94, Lys97, and Lys108.
  • RSPO3 epitope comprises one or more amino acids selected from Ser 49, Asn52, Cys54, Leu55, Ser56, Phe63, Leu65, Gln72, Ile73, Gly74, Tyr84, Tyr89, Pro90, Asp91, Ile92, Lys94, Lys97, and Lys108 of RSPO3.
  • the amino acid sequence of an exemplary human RSPO is RSPO1, for example, as shown in SEQ ID NO:3.
  • the amino acid sequence of an exemplary human RSPO is RSPO2, for example, as shown in SEQ ID NO:1.
  • the amino acid sequence of an exemplary human RSPO is RSPO3, for example, as shown in SEQ ID NO:2.
  • the amino acid sequence of an exemplary human RSPO is RSPO4, for example, as shown in SEQ ID NO:4.
  • anti-RSPO2 antibody and "an antibody that binds to RSPO2” refer to an antibody that is capable of binding RSPO2 with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting RSPO2.
  • the extent of binding of an anti-RSPO2 antibody to a non-RSP02 protein is less than about 10% of the binding of the antibody to RSPO2 as measured, e.g ., by a radioimmunoassay (RIA).
  • RIA radioimmunoassay
  • an antibody that binds to RSPO2 has a dissociation constant (Kd) of ⁇ 1 ⁇ M, ⁇ 100 nM, ⁇ 10 nM, ⁇ 1 nM, ⁇ 0.1 nM, ⁇ 0.01 nM, or ⁇ 0.001 nM ( e.g., 10 -8 M or less, e.g. from 10 -8 M to 10 -13 M, e.g., from 10 -9 M to 10 -13 M).
  • Kd dissociation constant
  • an anti-RSPO2 antibody binds to an epitope of RSPO2 that is conserved among RSPO2 from different species.
  • an antibody that binds to RSPO3 has a dissociation constant (Kd) of ⁇ 1 ⁇ M, ⁇ 100 nM, ⁇ 10 nM, ⁇ 1 nM, ⁇ 0.1 nM, ⁇ 0.01 nM, or ⁇ 0.001 nM ( e.g., 10 -8 M or less, e.g. from 10 -8 M to 10 -13 M, e.g., from 10 -9 M to 10 -13 M).
  • Kd dissociation constant
  • an anti-RSPO3 antibody binds to an epitope of RSPO3 that is conserved among RSPO3 from different species.
  • anti-RSPO2/3 antibody and "an antibody that binds to RSPO2 and RSPO3” refer to an antibody that is capable of binding RSPO2 and RSPO3 with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting RSPO2 and RSPO3.
  • the extent of binding of an anti-RSPO2/3 antibody to a non-RSPO2 or non-RSPO3 protein is less than about 10% of the binding of the antibody to RSPO2 and RSPO3 as measured, e.g., by a radioimmunoassay (RIA).
  • RIA radioimmunoassay
  • an antibody that binds to RSPO2 and RSPO3 has a dissociation constant (Kd) of ⁇ 1 ⁇ M, ⁇ 100 nM, ⁇ 10 nM, ⁇ 1 nM, ⁇ 0.1 nM, ⁇ 0.01 nM, or ⁇ 0.001 nM ( e.g., 10 -8 M or less, e.g. from 10 -8 M to 10 -13 M, e.g ., from 10 -9 M to 10 -13 M).
  • an anti-RSPO2/3 antibody binds to an epitope of RSPO2 and/or RSPO3 that is conserved among RSPO2 and/or RSPO3 from different species.
  • antibody herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g ., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity.
  • antibody fragment refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds.
  • antibody fragments include but are not limited to Fv, Fab, Fab', Fab'-SH, F(ab') 2 ; diabodies; linear antibodies; single-chain antibody molecules ( e . g ,. scFv); and multispecific antibodies formed from antibody fragments.
  • an "antibody that competes for binding with" a reference antibody refers to an antibody that blocks binding of the reference antibody to its antigen in a competition assay by 50% or more, and conversely, the reference antibody blocks binding of the antibody to its antigen in a competition assay by 50% or more.
  • An exemplary competition assay is provided herein.
  • the "class" of an antibody refers to the type of constant domain or constant region possessed by its heavy chain.
  • the heavy chain constant domains that correspond to the different classes of immunoglobulins are called ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ , respectively.
  • Fc region herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region.
  • the term includes native sequence Fc regions and variant Fc regions.
  • a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain.
  • the C-terminal lysine (Lys447) of the Fc region may or may not be present.
  • numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 .
  • FR Framework or "FR” refers to variable domain residues other than hypervariable region (HVR) residues.
  • the FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3, and FR4. Accordingly, the HVR and FR sequences generally appear in the following sequence in VH (or VL): FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.
  • full length antibody “intact antibody,” and “whole antibody” are used herein interchangeably to refer to an antibody having a structure substantially similar to a native antibody structure or having heavy chains that contain an Fc region as defined herein.
  • a "human antibody” is one which possesses an amino acid sequence which corresponds to that of an antibody produced by a human or a human cell or derived from a non-human source that utilizes human antibody repertoires or other human antibody-encoding sequences. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues.
  • a “humanized” antibody refers to a chimeric antibody comprising amino acid residues from non-human HVRs and amino acid residues from human FRs.
  • a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody, and all or substantially all of the FRs correspond to those of a human antibody.
  • a humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody.
  • a "humanized form" of an antibody, e.g ., a non-human antibody refers to an antibody that has undergone humanization.
  • HVR residues comprise those identified in Figures 9A-B and/or Figures 10A-B or elsewhere in the specification.
  • an “immunoconjugate” is an antibody conjugated to one or more heterologous molecule(s), including but not limited to a cytotoxic agent.
  • isolated nucleic acid encoding an anti-RSPO2 antibody refers to one or more nucleic acid molecules encoding antibody heavy and light chains (or fragments thereof), including such nucleic acid molecule(s) in a single vector or separate vectors, and such nucleic acid molecule(s) present at one or more locations in a host cell.
  • isolated nucleic acid encoding an anti-RSPO3 antibody refers to one or more nucleic acid molecules encoding antibody heavy and light chains (or fragments thereof), including such nucleic acid molecule(s) in a single vector or separate vectors, and such nucleic acid molecule(s) present at one or more locations in a host cell.
  • monoclonal antibody refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and/or bind the same epitope, except for possible variant antibodies, e.g ., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts.
  • polyclonal antibody preparations typically include different antibodies directed against different determinants (epitopes)
  • each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen.
  • the modifier "monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, such methods and other exemplary methods for making monoclonal antibodies being described herein.
  • naked antibody refers to an antibody that is not conjugated to a heterologous moiety (e.g ., a cytotoxic moiety) or radiolabel.
  • the naked antibody may be present in a pharmaceutical formulation.
  • Native antibodies refer to naturally occurring immunoglobulin molecules with varying structures.
  • native IgG antibodies are heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light chains and two identical heavy chains that are disulfide-bonded. From N- to C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or a heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3).
  • VH variable region
  • VL variable region
  • the light chain of an antibody may be assigned to one of two types, called kappa ( ⁇ ) and lambda ( ⁇ ), based on the amino acid sequence of its constant domain.
  • package insert is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and/or warnings concerning the use of such therapeutic products.
  • Percent (%) amino acid sequence identity with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.
  • % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2.
  • the ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087.
  • the ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California, or may be compiled from the source code.
  • the ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.
  • the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B is calculated as follows: 100 times the fraction X/Y where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of A and B, and where Y is the total number of amino acid residues in B.
  • R-spondin translocation and "RSPO translocation” refer herein to an R-spondin wherein a portion of a broken chromosome including, for example, R-spondin, variant, or fragment thereof or a second gene, variant, or fragment thereof, reattaches in a different chromosome location, for example, a chromosome location different from R-spondin native location or a chromosome location in and/or around the R-spondin native location which is different from the second gene's native location.
  • the R-spondin translocation may be a RSPO1 translocation, RSPO2 translocation, RSPO3 translocation, and/or RSPO4 translocation.
  • R-spondin-translocation fusion polynucleotide and "RSPO-translocation fusion polynucleotide” refer herein to the nucleic acid sequence of an R-spondin translocation gene product or fusion polynucleotide.
  • the R-spondin-translocation fusion polynucleotide may be a RSPO1-translocation fusion polynucleotide, RSPO2-translocation fusion polynucleotide, RSPO3-translocation fusion polynucleotide, and/or RSPO4-translocation fusion polynucleotide.
  • R-spondin-translocation fusion polypeptide and "RSPO-translocation fusion polypeptide” refer herein to the amino acid sequence of an R-spondin translocation gene product or fusion polynucleotide.
  • the R-spondin-translocation fusion polypeptide may be a RSPO1-translocation fusion polypeptide, RSPO2-translocation fusion polypeptide, RSP03-translocation fusion polypeptide, and/or RSPO4-translocation fusion polypeptide.
  • detection includes any means of detecting, including direct and indirect detection.
  • biomarker refers to an indicator, e.g ., a predictive, diagnostic, and/or prognostic indicator, which can be detected in a sample.
  • the biomarker may serve as an indicator of a particular subtype of a disease or disorder (e.g ., cancer) characterized by certain, molecular, pathological, histological, and/or clinical features.
  • the biomarker is a gene.
  • the biomarker is a variation (e.g ., mutation and/or polymorphism) of a gene.
  • the biomarker is a translocation.
  • Biomarkers include, but are not limited to, polynucleotides (e.g ., DNA, and/or RNA), polypeptides, polypeptide and polynucleotide modifications (e.g ., posttranslational modifications), carbohydrates, and/or glycolipid-based molecular markers.
  • the "presence,” “amount,” or “level” of a biomarker associated with an increased clinical benefit to an individual is a detectable level in a sample. These can be measured by methods known to one skilled in the art and also disclosed herein. The expression level or amount of biomarker assessed can be used to determine the response to the treatment.
  • Fragments of the transcribed polynucleotide, the translated polypeptide, or polynucleotide and/or polypeptide modifications shall also be regarded as expressed whether they originate from a transcript generated by alternative splicing or a degraded transcript, or from a posttranslational processing of the polypeptide, e.g ., by proteolysis.
  • "Expressed genes” include those that are transcribed into a polynucleotide as mRNA and then translated into a polypeptide, and also those that are transcribed into RNA but not translated into a polypeptide (for example, transfer and ribosomal RNAs).
  • Elevated expression refers to increased expression or increased levels of a biomarker in an individual relative to a control, such as an individual or individuals who are not suffering from the disease or disorder (e.g ., cancer) or an internal control (e.g ., housekeeping biomarker).
  • a control such as an individual or individuals who are not suffering from the disease or disorder (e.g ., cancer) or an internal control (e.g ., housekeeping biomarker).
  • Reduced expression refers to decrease expression or decreased levels of a biomarker in an individual relative to a control, such as an individual or individuals who are not suffering from the disease or disorder (e.g ., cancer) or an internal control (e.g ., housekeeping biomarker).
  • a control such as an individual or individuals who are not suffering from the disease or disorder (e.g ., cancer) or an internal control (e.g ., housekeeping biomarker).
  • housekeeping biomarker refers to a biomarker or group of biomarkers (e.g ., polynucleotides and/or polypeptides) which are typically similarly present in all cell types.
  • the housekeeping biomarker is a "housekeeping gene.”
  • a "housekeeping gene” refers herein to a gene or group of genes which encode proteins whose activities are essential for the maintenance of cell function and which are typically similarly present in all cell types.
  • a “reference sample”, “reference cell”, “reference tissue”, “control sample”, “control cell”, or “control tissue”, as used herein, refers to a sample, cell, tissue, standard, or level that is used for comparison purposes.
  • a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and/or non-diseased part of the body (e.g., tissue or cells) of the same subject or individual.
  • healthy and/or non-diseased cells or tissue adjacent to the diseased cells or tissue e.g ., cells or tissue adjacent to a tumor.
  • a reference sample is obtained from an untreated tissue and/or cell of the body of the same subject or individual.
  • substantially different refers to a sufficiently high degree of difference between two numeric values (generally one associated with a molecule and the other associated with a reference/comparator molecule) such that one of skill in the art would consider the difference between the two values to be of statistical significance within the context of the biological characteristic measured by said values (e.g., Kd values).
  • the difference between said two values may be, for example, greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, and/or greater than about 50% as a function of the value for the reference/comparator molecule.
  • chemotherapeutic agent refers to a chemical compound useful in the treatment of cancer.
  • examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapachone; lapachol; colchicines; betulinic acid; a camptothecin (including the synthetic analogue topotecan (HYCAMTIN®
  • celecoxib or etoricoxib proteosome inhibitor
  • proteosome inhibitor e.g. PS341
  • bortezomib VELCADE®
  • CCI-779 tipifarnib (R11577); orafenib, ABT510
  • Bcl-2 inhibitor such as oblimersen sodium (GENASENSE®)
  • pixantrone EGFR inhibitors (see definition below); tyrosine kinase inhibitors (see definition below); serine-threonine kinase inhibitors such as rapamycin (sirolimus, RAPAMUNE®); farnesyltransferase inhibitors such as lonafarnib (SCH 6636, SARASARTM); and pharmaceutically acceptable salts, acids or derivatives of any of the above; as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine
  • Chemotherapeutic agents as defined herein include “anti-hormonal agents” or “endocrine therapeutics” which act to regulate, reduce, block, or inhibit the effects of hormones that can promote the growth of cancer. They may be hormones themselves, including, but not limited to: anti-estrogens with mixed agonist/antagonist profile, including, tamoxifen (NOLVADEX®), 4-hydroxytamoxifen, toremifene (FARESTON®), idoxifene, droloxifene, raloxifene (EVISTA®), trioxifene, keoxifene, and selective estrogen receptor modulators (SERMs) such as SERM3; pure anti-estrogens without agonist properties, such as fulvestrant (FASLODEX®), and EM800 (such agents may block estrogen receptor (ER) dimerization, inhibit DNA binding, increase ER turnover, and/or suppress ER levels); aromatase inhibitors, including steroidal aromatase inhibitors such as forme
  • cytostatic agent refers to a compound or composition which arrests growth of a cell either in vitro or in vivo.
  • a cytostatic agent may be one which significantly reduces the percentage of cells in S phase.
  • Further examples of cytostatic agents include agents that block cell cycle progression by inducing G0/G1 arrest or M-phase arrest.
  • the humanized anti-Her2 antibody trastuzumab (HERCEPTIN®) is an example of a cytostatic agent that induces G0/G1 arrest.
  • Classical M-phase blockers include the vincas (vincristine and vinblastine), taxanes, and topoisomerase II inhibitors such as doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin.
  • Certain agents that arrest G1 also spill over into S-phase arrest, for example, DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C.
  • Taxanes are anticancer drugs both derived from the yew tree.
  • Docetaxel (TAXOTERE®, Rhone-Poulenc Rorer), derived from the European yew, is a semisynthetic analogue of paclitaxel (TAXOL®, Bristol-Myers Squibb). Paclitaxel and docetaxel promote the assembly of microtubules from tubulin dimers and stabilize microtubules by preventing depolymerization, which results in the inhibition of mitosis in cells.
  • EGFR inhibitor refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity, and is alternatively referred to as an "EGFR antagonist.”
  • EGFR antagonist examples include antibodies and small molecules that bind to EGFR.
  • antibodies which bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, US Patent No. 4,943, 533, Mendelsohn et al.
  • chimerized 225 C225 or Cetuximab; ERBUTIX®
  • H225 reshaped human 225
  • IMC-11F8 a fully human, EGFR-targeted antibody (Imclone); antibodies that bind type II mutant EGFR ( US Patent No. 5,212,290 ); humanized and chimeric antibodies that bind EGFR as described in US Patent No.
  • EMD 55900 Stragliotto et al. Eur. J. Cancer 32A:636-640 (1996 )
  • EMD7200 a humanized EGFR antibody directed against EGFR that competes with both EGF and TGF-alpha for EGFR binding
  • EMD/Merck human EGFR antibody
  • HuMax-EGFR HuMax-EGFR
  • the anti-EGFR antibody may be conjugated with a cytotoxic agent, thus generating an immunoconjugate (see, e.g., EP659,439A2 , Merck Patent GmbH).
  • EGFR antagonists include small molecules such as compounds described in US Patent Nos: 5,616,582 , 5,457,105 , 5,475,001 , 5,654,307 , 5,679,683 , 6,084,095 , 6,265,410 , 6,455,534 , 6,521,620 , 6,596,726 , 6,713,484 , 5,770,599 , 6,140,332 , 5,866,572 , 6,399,602 , 6,344,459 , 6,602,863 , 6,391,874 , 6,344,455 , 5,760,041 , 6,002,008 , and 5,747,498 , as well as the following PCT publications: WO98/14451 , WO98/50038 , WO99/09016 , and WO99/24037 .
  • EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA® Genentech/OSI Pharmaceuticals); PD 183805 (CI 1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSAJ) 4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperid
  • tumor refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.
  • cancer refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.
  • cancer refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.
  • cell proliferative disorder and “proliferative disorder” refer to disorders that are associated with some degree of abnormal cell proliferation.
  • the cell proliferative disorder is cancer.
  • cancer and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth/proliferation.
  • examples of cancer include, but are not limited to, carcinoma, lymphoma (e.g ., Hodgkin's and non-Hodgkin's lymphoma), blastoma, sarcoma, and leukemia.
  • cancers include squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, leukemia and other lymphoproliferative disorders, and various types of head and neck cancer.
  • colon tumor or “colon cancer” refers to any tumor or cancer of the colon (the large intestine from the cecum to the rectum).
  • colon tumor or “colorectal cancer” refers to any tumor or cancer of the large bowel, which includes the colon (the large intestine from the cecum to the rectum) and the rectum, including, e.g ., adenocarcinomas and less prevalent forms, such as lymphomas and squamous cell carcinomas.
  • an "effective amount" of an agent refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.
  • pharmaceutical formulation refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.
  • a “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject.
  • a pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.
  • mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g ., mice and rats).
  • domesticated animals e.g., cows, sheep, cats, dogs, and horses
  • primates e.g., humans and non-human primates such as monkeys
  • rabbits e.g ., mice and rats
  • rodents e.g ., mice and rats
  • anti-RSPO antibodies and uses thereof.
  • antibodies that bind to RSPO2 and/or RSPO3 are provided.
  • Antibodies provided are useful, e.g ., for the diagnosis or treatment of cancer, such as colorectal cancer.
  • the antibody binds to RSPO2. In some embodiments, the antibody binds to RSPO2 and do not significantly bind to RSPO3. In some embodiments, the antibody binds to RSPO3. In some embodiments, the antibody binds to RSPO3 and does not significantly bind to RSPO2. In some embodiments, the antibody binds to both RSPO2 and RSPO3. In some embodiments, the antibody is a multispecific antibody. In some embodiments, the multispecific antibody is a bispecific antibody. In some embodiments, the bispecific antibody comprises a first variable domain which binds to RSPO2 and a second variable domain which binds to RSPO3.
  • the antibody that binds to RSPO2 and/or RSPO3 is an antibody that binds RSPO2.
  • the anti-RSPO2 antibody binds RSPO2, wherein the RSPO2 has the sequence set forth in SEQ ID NO:1.
  • the anti-RSPO2 antibody binds RSPO2, wherein the RSPO2 lacks the signaling peptide sequence ( e.g ., binds to amino acids within amino acids 22-243 of SEQ ID NO:1).
  • the anti-RSPO2 antibody binds to one or more furin-like cysteine-rich domains of RSPO2.
  • the anti-RSPO2 antibody induces and/or promotes cancer cell (e.g., cancer stem cell) differentiation (e.g., terminal differentiation and/or differentiation into progenitor cell).
  • the anti-RSPO3 antibody induces and/or promotes cancer cell (e.g., cancer stem cell) differentiation into enterocyte, goblet cell, and/or enteroendocrine cell.
  • the antibody that binds to RSPO2 and/or RSPO3 is an antibody that binds RSPO3.
  • the anti-RSPO3 antibody binds RSPO3, wherein the RSPO3 has the sequence set forth in SEQ ID NO:2.
  • the anti-RSPO3 antibody binds RSPO3, wherein the RSPO3 lacks the signaling peptide sequence ( e.g ., binds to amino acids within amino acids 22-272 of SEQ ID NO:2).
  • the anti-RSPO3 antibody binds to one or more furin-like cysteine-rich domains of RSPO3.
  • the anti-RSPO3 antibody binds to an epitope comprising one or more amino acids selected from Ser49, Asn52, Cys54, Leu55, Ser56, Phe63, Leu65, Gln72, Ile73, Gly74, Tyr84, Tyr89, Pro90, Asp91, Ile92, Lys94, Lys97, and Lys108 of RSPO3 (e.g., SEQ ID NO:2).
  • the anti-RSPO3 antibody when bound to RSPO3 is positioned 4 angstroms or less from amino acids residues of RSPO3 (e.g., SEQ ID NO:2): Ser 49, Asn52, Cys54, Leu55, Ser56, Phe63, Leu65, Gln72, Ile73, Gly74, Tyr84, Tyr89, Pro90, Asp91, Ile92, Lys94, Lys97,and Lys108.
  • amino acids residues of RSPO3 e.g., SEQ ID NO:2: Ser 49, Asn52, Cys54, Leu55, Ser56, Phe63, Leu65, Gln72, Ile73, Gly74, Tyr84, Tyr89, Pro90, Asp91, Ile92, Lys94, Lys97,and Lys108.
  • the anti-RSPO3 antibody binds to amino acids within amino acids 47 to 108 of SEQ ID NO:2. In some embodiments, the anti-RSPO3 antibody binds to an epitope comprising one or more amino acids selected from Thr47, Asn52, Cys54, Leu55, Ser56, Phe63, Leu65, Gln72, Tyr84, Tyr89, Pro90, Asp91, Ile92, Asn93, Lys94, Lys97, and Lys108 of RSPO3 (e.g., SEQ ID NO:2).
  • the anti-RSPO3 antibody binds to an epitope comprising amino acids residues of RSP03 (e.g., SEQ ID NO:2): Thr47, Asn52, Cys54, Leu55, Ser56, Phe63, Leu65, Gln72, Tyr84, Tyr89, Pro90, Asp91, Ile92, Asn93, Lys94, Lys97, and Lys108.
  • RSP03 amino acids residues of RSP03
  • the anti-RSPO2/3 antibody inhibits the interaction of RSPO2 and RSPO3 with one or more of LGR4, LGR5, and/or LGR6.
  • the antibody is a dual arm antibody.
  • the anti-RSPO2/3 antibody comprises a first and second variable domain comprising on each variable domain the six HVRs of 26E11.
  • the antibody is a bispecific antibody.
  • the anti-RSPO2/3 antibody comprises a first variable domain comprising the six HVRs of 5D6 or 5E11 and a second variable domain comprising the six HVRs of 36D2.
  • the epitope is a conformational epitope. In some embodiments, the epitope is determined by antibody binding to peptide fragments. In some embodiments, the epitope is determined by mass spectrometry. In some embodiments, the epitope is determined by crystallography (e.g., analysis of crystal structure).
  • the invention provides an anti-RSPO3 antibody comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:8; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:9; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:10; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:7.
  • the invention provides an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:8; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:9; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:10.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:10.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:10 and HVR-L3 comprising the amino acid sequence of SEQ ID NO:7.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:10, HVR-L3 comprising the amino acid sequence of SEQ ID NO:7, and HVR-H2 comprising the amino acid sequence of SEQ ID NO:9.
  • the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:8; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:9; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:10.
  • the invention provides an antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:7.
  • the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:7.
  • an antibody of the invention comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:8, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:9, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO:10; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:7.
  • the invention provides an anti-RSPO3 antibody comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:14; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:15; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:16; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:11; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:12; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:13.
  • the invention provides an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:14; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:15; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:16.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:16.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:16 and HVR-L3 comprising the amino acid sequence of SEQ ID NO:13.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:16, HVR-L3 comprising the amino acid sequence of SEQ ID NO:13, and HVR-H2 comprising the amino acid sequence of SEQ ID NO:15.
  • the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:14; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:15; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:16.
  • the invention provides an antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:11; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:12; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:13.
  • the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:11; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:12; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:13.
  • an antibody of the invention comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:14, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:15, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO:16; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:11, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:12, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:13.
  • the invention provides an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:14; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:15; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:16; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:11; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:12; and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:13.
  • an anti-RSP03 antibody comprising a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above.
  • the antibody comprises the VH and VL sequences in SEQ ID NO:91 and SEQ ID NO:92, respectively, including post-translational modifications of those sequences.
  • the invention provides an anti-RSPO3 antibody comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:20; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:21; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:22; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:17; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:18; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:19.
  • the invention provides an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:20; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:21; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:22.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:22.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:22 and HVR-L3 comprising the amino acid sequence of SEQ ID NO:19.
  • an antibody of the invention comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:20, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:21, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO:22; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:17, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:18, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:19.
  • the invention provides an anti-RSPO3 antibody comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:26; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:27; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:28; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:23; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:24; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:25.
  • HVR-H1 comprising the amino acid sequence of SEQ ID NO:26
  • HVR-H2 comprising the amino acid sequence of SEQ ID NO:27
  • HVR-H3 comprising the amino acid sequence of SEQ ID NO:28
  • HVR-L1 comprising the amino acid sequence of SEQ ID NO:23
  • HVR-L2 comprising
  • the invention provides an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:26; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:27; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:28.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:28.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:28 and HVR-L3 comprising the amino acid sequence of SEQ ID NO:25.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:28, HVR-L3 comprising the amino acid sequence of SEQ ID NO:25, and HVR-H2 comprising the amino acid sequence of SEQ ID NO:27.
  • the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:26; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:27; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:28.
  • the invention provides an antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:23; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:24; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:25.
  • the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:23; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:24; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:25.
  • an anti-RSP03 antibody comprising a VH as in any of the embodiments provided above, and a VL as in any of the embodiments provided above.
  • the antibody comprises the VH and VL sequences in SEQ ID NO:95 and SEQ ID NO:96, respectively, including post-translational modifications of those sequences.
  • the antibody comprises the VH and VL sequences in SEQ ID NO:198 and SEQ ID NO:199, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:200 and SEQ ID NO:201, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:202 and SEQ ID NO:203, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:204 and SEQ ID NO:205, respectively, including post-translational modifications of those sequences.
  • the antibody comprises the VH and VL sequences in SEQ ID NO:206 and SEQ ID NO:207, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:208 and SEQ ID NO:209, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:210 and SEQ ID NO:211, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:212 and SEQ ID NO:213, respectively, including post-translational modifications of those sequences. In one embodiment, the antibody comprises the VH and VL sequences in SEQ ID NO:214 and SEQ ID NO:215, respectively, including post-translational modifications of those sequences.
  • an anti-RSPO3 antibody is a monoclonal antibody, including a human antibody.
  • an anti-RSPO3 antibody is an antibody fragment, e.g., a Fv, Fab, Fab', scFv, diabody, or F(ab') 2 fragment.
  • the antibody is a substantially full length antibody, e.g., an IgG1 antibody, IgG2a antibody or other antibody class or isotype as defined herein.
  • the invention provides an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:32; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:33; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:34.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:34.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:34 and HVR-L3 comprising the amino acid sequence of SEQ ID NO:31.
  • the invention provides an antibody comprising (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:32; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:33; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:34; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:29; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:30; and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:31.
  • the invention provides an anti-RSPO3 antibody comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:38; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:39; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:40; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:35; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:36; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:37.
  • an antibody of the invention comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:38, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:39, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO:40; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:35, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:36, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:37.
  • the invention provides an anti-RSPO3 antibody comprising at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:44; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:45; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:46; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:41; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:42; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:43.
  • the invention provides an antibody comprising at least one, at least two, or all three VL HVR sequences selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:47; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:48; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:49.
  • the antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO:47; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO:48; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:49.
  • the invention provides an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:86; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:87; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:88.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:88.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:88 and HVR-L3 comprising the amino acid sequence of SEQ ID NO:85.
  • an antibody of the invention comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:86, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:87, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO:88; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:83, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:84, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO:85.
  • the invention provides an antibody comprising at least one, at least two, or all three VH HVR sequences selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:74; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:75; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:76.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:76.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:76 and HVR-L3 comprising the amino acid sequence of SEQ ID NO:73.
  • the antibody comprises HVR-H3 comprising the amino acid sequence of SEQ ID NO:76, HVR-L3 comprising the amino acid sequence of SEQ ID NO:73, and HVR-H2 comprising the amino acid sequence of SEQ ID NO:75.
  • the antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:74; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:75; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:76.
  • an antibody provided herein has a dissociation constant (Kd) of ⁇ 1 ⁇ M, ⁇ 100 nM, ⁇ 10 nM, ⁇ 1 nM, ⁇ 0.1 nM, ⁇ 0.01 nM, or ⁇ 0.001 nM ( e.g. 10 -8 M or less, e.g. from 10 -8 M to 10 -13 M, e.g ., from 10 -9 M to 10 -13 M).
  • Kd dissociation constant
  • repertoires of VH and VL genes are separately cloned by polymerase chain reaction (PCR) and recombined randomly in phage libraries, which can then be screened for antigen-binding phage as described in Winter et al., Ann. Rev. Immunol., 12: 433-455 (1994 ).
  • Phage typically display antibody fragments, either as single-chain Fv (scFv) fragments or as Fab fragments.
  • scFv single-chain Fv
  • Libraries from immunized sources provide high-affinity antibodies to the immunogen without the requirement of constructing hybridomas.
  • Asn297 refers to the asparagine residue located at about position 297 in the Fc region (Eu numbering of Fc region residues); however, Asn297 may also be located about ⁇ 3 amino acids upstream or downstream of position 297, i.e ., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function. See, e.g., US Patent Publication Nos. US 2003/0157108 (Presta, L.); US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd).
  • an antibody variant comprises an Fc region with one or more amino acid substitutions which improve ADCC, e.g ., substitutions at positions 298, 333, and/or 334 of the Fc region (EU numbering of residues).
  • Suitable host cells for the expression of glycosylated antibody are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. Numerous baculoviral strains have been identified which may be used in conjunction with insect cells, particularly for transfection of Spodoptera frugiperda cells.
  • Conjugates of an antibody and cytotoxic agent may be made using a variety of bifunctional protein coupling agents such as N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP), succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCl), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as
  • luciferin 2,3-dihydrophthalazinediones, horseradish peroxidase (HRP), alkaline phosphatase, ⁇ -galactosidase, glucoamylase, lysozyme, saccharide oxidases, e.g ., glucose oxidase, galactose oxidase, and glucose-6-phosphate dehydrogenase, heterocyclic oxidases such as uricase and xanthine oxidase, coupled with an enzyme that employs hydrogen peroxide to oxidize a dye precursor such as HRP, lactoperoxidase, or microperoxidase, biotin/avidin, spin labels, bacteriophage labels, stable free radicals, and the like.
  • HRP horseradish peroxidase
  • lactoperoxidase lactoperoxidase
  • microperoxidase biotin/avidin
  • spin labels bacteriophage labels
  • Presence and/or expression level/amount of various biomarkers in a sample can be analyzed by a number of methodologies, many of which are known in the art and understood by the skilled artisan, including, but not limited to, immunohistochemical ("IHC"), Western blot analysis, immunoprecipitation, molecular binding assays, ELISA, ELIFA, fluorescence activated cell sorting (“FACS”), MassARRAY, proteomics, quantitative blood based assays (as for example Serum ELISA), biochemical enzymatic activity assays, in situ hybridization, Southern analysis, Northern analysis, whole genome sequencing, polymerase chain reaction (“PCR”) including quantitative real time PCR (“qRT-PCR”) and other amplification type detection methods, such as, for example, branched DNA, SISBA, TMA and the like), RNA-Seq, FISH, microarray analysis, gene expression profiling, and/or serial analysis of gene expression (“SAGE”), as well as any one of the wide variety of assays that can be
  • the invention provides for the use of an anti-RSPO antibody in the manufacture or preparation of a medicament.
  • the medicament is for treatment of tumor, cell proliferative disorder, and/or cancer.
  • the medicament is for use in a method of treating tumor, cell proliferative disorder, and/or cancer comprising administering to an individual having tumor, cell proliferative disorder, and/or cancer an effective amount of the medicament.
  • the cancer is colorectal cancer.
  • the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, e.g., as described below.
  • the medicament is for inhibiting wnt signaling, inhibiting angiogenesis, inhibiting cell proliferation, inhibiting cancer stem cell proliferation, and/or depleting cancer stem cells.
  • the medicament is for use in a method of inhibiting wnt signaling, inhibiting angiogenesis, inhibiting cell proliferation, inhibiting cancer stem cell proliferation, and/or depleting cancer stem cells in an individual comprising administering to the individual an amount effective of the medicament to inhibit wnt signaling, inhibit angiogenesis, inhibit cell proliferation, inhibit cancer stem cell proliferation, and/or deplete cancer stem cells.
  • An "individual" according to any of the above embodiments may be a human. In some embodiments, the individual and/or cancer has one or more biomarker.
  • the cancer is adrenal cancer, bladder cancer, brain cancer, breast cancer, cervix cancer, colon cancer, head and neck cancer, kidney cancer, leukemia, liver cancer, lung cancer (e.g ., NSCLC), lymphoid cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectum cancer, skin cancer (e.g., melanoma), stomach cancer, thyroid cancer, and/or uterine cancer.
  • the cancer is lung cancer (e.g ., NSCLC), ovarian cancer, breast cancer, liver cancer, or multiple myeloma.
  • transplanted PTPRK-RSPO fusion patient derived tumor models treated with an anti-RSPO3 antibody should have a reduced cancer stem cell population, which should reduce the establishment and tumor growth of serial PTPRK-RSPO fusion patient derived tumors.
  • anti-RSPO3 antibodies 5D6 results in fewer tumors being established and growing from anti-RSPO3 treated fragments following serial transplantation.

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Claims (21)

  1. Isolierter Antikörper, der an RSPO3 bindet, wobei der Antikörper Folgendes umfasst:
    (a) eine VL, umfassend (i) HVR-L1, umfassend die Aminosäuresequenz von SEQ ID NO:5, (ii) HVR-L2, umfassend die Aminosäuresequenz von SEQ ID NO:6, und (iii) HVR-L3, umfassend die Aminosäuresequenz von SEQ ID NO:7; und eine VH, umfassend (i) HVR-H1, umfassend die Aminosäuresequenz von SEQ ID NO:8, (ii) HVR-H2, umfassend die Aminosäuresequenz von SEQ ID NO:9, und (iii) HVR-H3, umfassend die Aminosäuresequenz von SEQ ID NO:10;
    (b) eine VL, umfassend (i) HVR-L1, umfassend die Aminosäuresequenz von SEQ ID NO:11, (ii) HVR-L2, umfassend die Aminosäuresequenz von SEQ ID NO:12, und (iii) HVR-L3, umfassend die Aminosäuresequenz von SEQ ID NO:13; und eine VH, umfassend (i) HVR-H1, umfassend die Aminosäuresequenz von SEQ ID NO:14, (ii) HVR-H2, umfassend die Aminosäuresequenz von SEQ ID NO:15, und (iii) HVR-H3, umfassend die Aminosäuresequenz von SEQ ID NO:16;
    (c) eine VL, umfassend (i) HVR-L1, umfassend die Aminosäuresequenz von SEQ ID NO:17, (ii) HVR-L2, umfassend die Aminosäuresequenz von SEQ ID NO:18, und (iii) HVR-L3, umfassend die Aminosäuresequenz von SEQ ID NO:19; und eine VH, umfassend (i) HVR-H1, umfassend die Aminosäuresequenz von SEQ ID NO:20, (ii) HVR-H2, umfassend die Aminosäuresequenz von SEQ ID NO:21, und (iii) HVR-H3, umfassend die Aminosäuresequenz von SEQ ID NO:22;
    (d) eine VL, umfassend (i) HVR-L1, umfassend die Aminosäuresequenz von SEQ ID NO:23, (ii) HVR-L2, umfassend die Aminosäuresequenz von SEQ ID NO:24, und (iii) HVR-L3, umfassend die Aminosäuresequenz von SEQ ID NO:25; und eine VH, umfassend (i) HVR-H1, umfassend die Aminosäuresequenz von SEQ ID NO:26, (ii) HVR-H2, umfassend die Aminosäuresequenz von SEQ ID NO:27, und (iii) HVR-H3, umfassend die Aminosäuresequenz von SEQ ID NO:28;
    (e) eine VL, umfassend (i) HVR-L1, umfassend die Aminosäuresequenz von SEQ ID NO:29, (ii) HVR-L2, umfassend die Aminosäuresequenz von SEQ ID NO:30, und (iii) HVR-L3, umfassend die Aminosäuresequenz von SEQ ID NO:31; und eine VH, umfassend (i) HVR-H1, umfassend die Aminosäuresequenz von SEQ ID NO:32, (ii) HVR-H2, umfassend die Aminosäuresequenz von SEQ ID NO:33, und (iii) HVR-H3, umfassend die Aminosäuresequenz von SEQ ID NO:34;
    (f) eine VL, umfassend (i) HVR-L1, umfassend die Aminosäuresequenz von SEQ ID NO:35, (ii) HVR-L2, umfassend die Aminosäuresequenz von SEQ ID NO:36, und (iii) HVR-L3, umfassend die Aminosäuresequenz von SEQ ID NO:37; und eine VH, umfassend (i) HVR-H1, umfassend die Aminosäuresequenz von SEQ ID NO:38, (ii) HVR-H2, umfassend die Aminosäuresequenz von SEQ ID NO:39, und (iii) HVR-H3, umfassend die Aminosäuresequenz von SEQ ID NO:40;
    (g) eine VL, umfassend (i) HVR-L1, umfassend die Aminosäuresequenz von SEQ ID NO:41, (ii) HVR-L2, umfassend die Aminosäuresequenz von SEQ ID NO:42, und (iii) HVR-L3, umfassend die Aminosäuresequenz von SEQ ID NO:43; und eine VH, umfassend (i) HVR-H1, umfassend die Aminosäuresequenz von SEQ ID NO:44, (ii) HVR-H2, umfassend die Aminosäuresequenz von SEQ ID NO:45, und (iii) HVR-H3, umfassend die Aminosäuresequenz von SEQ ID NO:46;
    (h) eine VL, umfassend (i) HVR-L1, umfassend die Aminosäuresequenz von SEQ ID NO:23, (ii) HVR-L2, umfassend die Aminosäuresequenz von SEQ ID NO:24, und (iii) HVR-L3, umfassend die Aminosäuresequenz von SEQ ID NO:25; und eine VH, umfassend (i) HVR-H1, umfassend die Aminosäuresequenz von SEQ ID NO:26, (ii) HVR-H2, umfassend die Aminosäuresequenz von SEQ ID NO:27, und (iii) HVR-H3, umfassend die Aminosäuresequenz von SEQ ID NO:188;
    (i) eine VL, umfassend (i) HVR-L1, umfassend die Aminosäuresequenz von SEQ ID NO:23, (ii) HVR-L2, umfassend die Aminosäuresequenz von SEQ ID NO:24, und (iii) HVR-L3, umfassend die Aminosäuresequenz von SEQ ID NO:25; und eine VH, umfassend (i) HVR-H1, umfassend die Aminosäuresequenz von SEQ ID NO:26, (ii) HVR-H2, umfassend die Aminosäuresequenz von SEQ ID NO:27, und (iii) HVR-H3, umfassend die Aminosäuresequenz von SEQ ID NO:189;
    (j) eine VL, umfassend (i) HVR-L1, umfassend die Aminosäuresequenz von SEQ ID NO:77, (ii) HVR-L2, umfassend die Aminosäuresequenz von SEQ ID NO:78, und (iii) HVR-L3, umfassend die Aminosäuresequenz von SEQ ID NO:79; und eine VH, umfassend (i) HVR-H1, umfassend die Aminosäuresequenz von SEQ ID NO:80, (ii) HVR-H2, umfassend die Aminosäuresequenz von SEQ ID NO:81, und (iii) HVR-H3, umfassend die Aminosäuresequenz von SEQ ID NO:82;
    (k) eine VL, umfassend (i) HVR-L1, umfassend die Aminosäuresequenz von SEQ ID NO:83, (ii) HVR-L2, umfassend die Aminosäuresequenz von SEQ ID NO:84, und (iii) HVR-L3, umfassend die Aminosäuresequenz von SEQ ID NO:85; und eine VH, umfassend (i) HVR-H1, umfassend die Aminosäuresequenz von SEQ ID NO:86, (ii) HVR-H2, umfassend die Aminosäuresequenz von SEQ ID NO:87, und (iii) HVR-H3, umfassend die Aminosäuresequenz von SEQ ID NO:88 oder
    (l) eine VL, umfassend (i) HVR-L1, umfassend die Aminosäuresequenz von SEQ ID NO:77, (ii) HVR-L2, umfassend die Aminosäuresequenz von SEQ ID NO:78, und (iii) HVR-L3, umfassend die Aminosäuresequenz von SEQ ID NO:79; und eine VH, umfassend (i) HVR-H1, umfassend die Aminosäuresequenz von SEQ ID NO:80, (ii) HVR-H2, umfassend die Aminosäuresequenz von SEQ ID NO:81, und (iii) HVR-H3, umfassend die Aminosäuresequenz von SEQ ID NO:216.
  2. Isolierter Antikörper nach Anspruch 1, wobei der Antikörper Folgendes umfasst
    (a) eine VL-Sequenz von SEQ ID NO:89 und eine VH-Sequenz von SEQ ID NO:90;
    (b) eine VL-Sequenz von SEQ ID NO:91 und eine VH-Sequenz von SEQ ID NO:92;
    (c) eine VL-Sequenz von SEQ ID NO:93 und eine VH-Sequenz von SEQ ID NO:94;
    (d) eine VL-Sequenz von SEQ ID NO:95 und eine VH-Sequenz von SEQ ID NO:96;
    (e) eine VL-Sequenz von SEQ ID NO:97 und eine VH-Sequenz von SEQ ID NO:98;
    (f) eine VL-Sequenz von SEQ ID NO:99 und eine VH-Sequenz von SEQ ID NO:100;
    (g) eine VL-Sequenz von SEQ ID NO:101 und eine VH-Sequenz von SEQ ID NO:102;
    (h) eine VL-Sequenz von SEQ ID NO:190 und eine VH-Sequenz von SEQ ID NO:191;
    (i) eine VL-Sequenz von SEQ ID NO:192 und eine VH-Sequenz von SEQ ID NO:193;
    (j) eine VL-Sequenz von SEQ ID NO:194 und eine VH-Sequenz von SEQ ID NO:195;
    (k) eine VL-Sequenz von SEQ ID NO:196 und eine VH-Sequenz von SEQ ID NO:197;
    (l) eine VL-Sequenz von SEQ ID NO:198 und eine VH-Sequenz von SEQ ID NO:199;
    (m) eine VL-Sequenz von SEQ ID NO:200 und eine VH-Sequenz von SEQ ID NO:201;
    (n) eine VL-Sequenz von SEQ ID NO:202 und eine VH-Sequenz von SEQ ID NO:203;
    (o) eine VL-Sequenz von SEQ ID NO:204 und eine VH-Sequenz von SEQ ID NO:205;
    (p) eine VL-Sequenz von SEQ ID NO:206 und eine VH-Sequenz von SEQ ID NO:207;
    (q) eine VL-Sequenz von SEQ ID NO:208 und eine VH-Sequenz von SEQ ID NO:209;
    (r) eine VL-Sequenz von SEQ ID NO:210 und eine VH-Sequenz von SEQ ID NO:211;
    (w) eine VL-Sequenz von SEQ ID NO:212 und eine VH-Sequenz von SEQ ID NO:213 oder
    (x) eine VL-Sequenz von SEQ ID NO:214 und eine VH-Sequenz von SEQ ID NO:215.
  3. Antikörper nach Anspruch 1 oder 2, wobei der Antikörper die Wechselwirkung von RSPO3 mit einer Transmembran-E3-Ubiquitinase inhibiert.
  4. Isolierter Antikörper nach Anspruch 3, wobei die Transmembran-E3-Ubiquitinase ZNRF3 und/oder RNF43 ist.
  5. Isolierter Antikörper nach einem der Ansprüche 1-4, wobei der Antikörper RSPO3-vermittelte Wnt-Signalisierung inhibiert.
  6. Isolierter Antikörper nach einem der Ansprüche 1-5, der ein Antikörperfragment ist, das RSPO3 bindet.
  7. Antikörper nach einem der Ansprüche 1-6, der ein monoklonaler Antikörper ist.
  8. Antikörper nach einem der Ansprüche 1-7, der ein humanisierter oder chimärer Antikörper ist.
  9. Antikörper nach einem der Ansprüche 1-8, der ein IgG1- oder IgG2a-Antikörper voller Länge ist.
  10. Isolierte Nukleinsäure, die für den Antikörper nach einem der Ansprüche 1-9 kodiert.
  11. Wirtszelle, umfassend die Nukleinsäure nach Anspruch 10.
  12. Verfahren zum Produzieren eines Antikörpers, umfassend das Kultivieren der Wirtszelle nach Anspruch 11, so dass der Antikörper produziert wird.
  13. Verfahren nach Anspruch 12, ferner umfassend das Gewinnen des Antikörpers aus der Wirtszelle.
  14. Immunkonjugat, umfassend den Antikörper nach einem der Ansprüche 1-9 und ein zytotoxisches Mittel.
  15. Pharmazeutische Formulierung, umfassend den Antikörper nach einem der Ansprüche 1-9 und einen pharmazeutisch unbedenklichen Träger.
  16. Pharmazeutische Formulierung nach Anspruch 15, ferner umfassend ein zusätzliches Therapeutikum.
  17. Antikörper nach einem der Ansprüche 1-9 zur Verwendung als ein Medikament.
  18. Antikörper nach einem der Ansprüche 1-9 zur Verwendung bei der Behandlung von Krebs.
  19. Antikörper nach Anspruch 18, wobei der Krebs Magen-Darm-Krebs, Magenkrebs, Kolonkrebs, Dickdarmkrebs, Lungenkrebs oder Rektumkrebs ist.
  20. Antikörper nach einem der Ansprüche 1-9 zur Verwendung beim Inhibieren von Wnt-Signalisierung, Inhibieren von Angiogenese und/oder Gefäßneubildung und/oder Inhibieren von Zellproliferation, sofern diese in pathologischen Zuständen auftreten.
  21. Antikörper nach einem der Ansprüche 18-19, wobei der Krebs durch eine RSPO-Translokation gekennzeichnet ist.
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